The ability of either cocaine or amphetamine to enhance monoaminergic neurotransmission via inhibition of neuronal uptake is thought to be one mechanism that contributes to their psychotropic properties. The proposed experimental plan seeks to understand potential changes in synaptic neurobiology as a consequence of increased transmitter levels. Specifically, studies are proposed to 1) define the interaction of serotonin (5HT) and dopamine (DA) in areas of the brain relevant to drug self-administration such as the medial prefrontal cortex and nucleus accumbens, 2) determine the consequence of repeated cocaine or amphetamine on presynaptic autoreceptor function, postsynaptic DA sensitive adenylate cyclase, and the relative balance of D1/D2 influence at each site, 3) define further the mechanisms by which amphetamine and cocaine alter DA or 5HT synthesis in intact nerve terminals. Objectives will be realized with a combination of neurochemical techniques, including DA and 5HT synthesis in vivo, synthesis and release in striatal brain slices in vitro, brain microdialysis to measure transmitter release in vivo, and adenylate cyclase determinations. Advances in understanding the neurobiology of cocaine and amphetamine have not kept pace with the exponential increase in drug abuse. Nonetheless, successful, pharmacological-based withdrawal programs for drug abstinence require knowledge of the molecular mechanisms associated with drug self- administration and craving. By examining the effects of both acute and chronic exposure to these drugs of abuse, the proposed experiments will yield insight into both the mechanism of action and the functional consequences of stimulant abuse.